Honorary Professor Garry Graham.

An appreciation of the contribution of Professor Gary Graham to anti-inflammatory and antirheumatic pharmacology and clinical pharmacology.

Medical Cannabis: A plurimillennial history of an evergreen.

The history of Cannabis goes along that of humankind, as speculated based on geographical and evolutionary models together with historic data collected to date. Its medical use is several thousand years old, as attested both by archeobotanical evidence of Cannabis remains and written records found in ancient texts from the sacred Vedic foundational texts of Ayurvedic medicine (about 800 before current era [BCE]) to the first known Pharmacopoea, the Chinese "Shen Nung Pen Ts'ao Ching" (1 century BCE). In this paper, we retrace the history of Cannabis traveling through the key stages of its diffusion among the most important ancient cultures up to our days, when we are facing a renaissance of its medical employment. We report through the centuries evidence of its use in numerous pathologic conditions especially for its anti-inflammatory, antiseptic, and anticonvulsing properties that support the requirement to direct our present research efforts into the definitive understanding of its efficacy.

Heparin: 100 years of pleiotropic effects.

Heparin is a glycosaminoglycan with anticoagulant properties and antiinflammatory effects. The discovery of heparin approaches its 100th year and its antiinflammatory properties still draws much attention and anticipation to new possibilities of use and the likelihood of developing heparin-like drugs that lacked the anticoagulation effects. It is known that heparins limit the embolization and the extension of the thrombus, although they do not promote its complete lysis in most cases. The complexity and pleiotropic characteristics of these glycosaminoglycans still challenge science, to the point in which approaches hitherto unusual appear repeatedly in the literature. New indications, accompanied by longtime consecrated others, dismantle the idea of an outdated medication and create high expectations for the near future. The objective of this review is to analyze the pleiotropic effects of heparin and its use in several diseases, highlighting its safety and effectiveness.

The History of Cortisone Discovery and Development.

Philip Hench, Edward Kendall, and Tadeus Reichstein received the Nobel Prize in medicine and physiology in 1950 for their "investigations of the hormones of the adrenal cortex." Hench and Kendall took compound E from the laboratory to the clinic to the Nobel Prize in a span of 2 years. This article examines the paths that led to the day when the first rheumatoid arthritis patient received cortisone, and from there to the 1950 Nobel Prize ceremony. The aftermath of this achievement is also discussed. Although there have been significant advances in corticosteroid preparations and use since 1950, the side effects remain daunting.

[The history of the Science of Stress: From Hans Selye to the discovery of anti-inflammatory medication]. / L'histoire de la science du stress : de Hans Selye à la découverte des anti-inflammatoires.

To make an important scientific discovery that will make history takes a lot of determination, creativity, perseverance and luck! The story behind the discovery of stress and its biological basis is a fascinating one that places Dr. Hans Selye in the forefront. Dr. Selye was a great scientist that taught at the Université de Montréal from 1945 to his death in 1982. Dr. Selye was curious and hard working. He was determined to understand how various disorders can lead to similar physical manifestations, and this interest led him to discover the role of the adrenal glands involved in the stress response and to better understand the effects of glucocorticoids on the body. Today, the science of stress is based on the foundations established by Dr. Selye. In celebration of the 50th anniversary of the Département de psychiatrie de l'Université de Montréal, and the special issue of the Revue Santé Mentale au Québec, this historical review summarizes the discoveries of this great scientist who worked in Quebec.

A short history of biological therapy for psoriatic arthritis.

Psoriatic arthritis (PsA) is an inflammatory disease characterised by the clinical domains of arthritis, enthesitis, dactylitis, spondylitis, and psoriasis, often causing significant functional disability, loss of quality of life, and premature mortality. Prior to the introduction of targeted biologic medications, such as TNF inhibitors, the capacity to control disease activity was limited, with only modest effects noted in most patients with traditional oral medications such as methotrexate and sulfasalazine. The introduction of TNF inhibitors substantially changed the outlook of PsA patients, yielding significant response in all relevant clinical domains and demonstrating the capacity to inhibit progressive structural damage of joints. However, not all patients responded to these agents and many patients displayed initial response which waned over time, partly due to immunogenicity (development of antibodies which blocked full therapeutic effect of the biologic protein), or because of poor tolerability and/or adverse events. Thus, it has been important to develop new medicines which target other key cytokines and immunologic pathways, including ustekinumab which inhibits both IL12 and IL23 and thus is felt to work in both the TH1 and TH7 pathways of inflammation, has been approved for the treatment of PsA as well as psoriasis. IL17 inhibitors, including secukinumab and ixekizumab have demonstrated significant effectiveness in psoriasis and PsA; abatacept, which modulates T cell activity via inhibition the second signal of T cell activation is under study. This article provides an historical overview of this revolution; details of specific biological therapies will be provided in adjacent articles in this supplement.

From plant extract to molecular panacea: a commentary on Stone (1763) 'An account of the success of the bark of the willow in the cure of the agues'.

The application of aspirin-like drugs in modern medicine is very broad, encompassing the treatment of inflammation, pain and a variety of cardiovascular conditions. Although anecdotal accounts of willow bark extract as an anti-inflammatory drug have occurred since written records began (for example by Hippocrates), the first convincing demonstration of a potent anti-pyretic effect of willow bark containing salicylates was made by the English cleric Edward Stone in the late eighteenth century. Here, we discuss the route to optimizing and understanding the mechanism of action of anti-inflammatory drugs that have their origins in Stone's seminal study, 'An account of the success of the bark of the willow in the cure of agues'. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.

New drugs from ancient natural foods. Oleocanthal, the natural occurring spicy compound of olive oil: a brief history.

Extra-virgin olive oil (EVOO), a principal component of the Mediterranean diet (Med diet), is one of the most ancient known foods and has long been associated with health benefits. Many phenolic compounds extracted from Olea europea L. have attracted attention since their discovery. Among these phenolic constituents, oleocanthal has recently emerged as a potential therapeutic molecule for different diseases, showing relevant pharmacological properties in various pathogenic processes, including inflammation, cancers and neurodegenerative diseases. Here, we discuss and summarize the most recent pharmacological evidence for the medical relevance of oleocanthal, focusing our attention on its anti-inflammatory and chemotherapeutic roles.

Mary Allen Engle Award: The glue of life--a career retrospective.

The author was privileged to be an early contributor to the concept that cell adhesion molecules, the leukocyte (ß2) integrins, play a pivotal role in the acute inflammatory process. For the author, this began with the development of a monoclonal antibody (anti-Mo1) that identified a differentiation antigen on the surface of human myeloid cells (including neutrophils, monocytes, and natural killer (NK) cells). Serendipitously, it was discovered that the Mo1 antigen was the heterodimeric glycoprotein (gp155,95) absent from the surface of neutrophils isolated from patients with adhesion defects in vitro and a syndrome characterized by chronic, life-threatening infections in vivo (a syndrome now termed leukocyte adhesion deficiency, type 1) (LAD-1). Collaborative efforts with other investigators (including members of the ACCA) revealed that patients with LAD-1 exhibited genetic mutations on chromosome 21 resulting in absent or diminished expression of a class of 4 surface adhesion molecules (now termed CD11a/CD18, CD11b/CD18, CD11c/CD18, and CD11d/CD18) known as the leukocyte or ß2 family of integrins. Knowledge of the role of the ß2 integrins in the acute inflammatory response led to the development of effective gene therapy strategies to treat LAD-1 in preclinical animal models and to the comprehensive testing of anti-integrin antibodies as anti-inflammatory agents to prevent organ damage as a complication of acute inflammation. This retrospective provides one illustration of the potential of bench-to-bedside research to generate new knowledge of clinical significance.

[A short history of anti-rheumatic therapy. IV. Corticosteroids]. / Piccola storia della terapia antireumatica. IV. I cortisonici.

In 1948 a corticosteroid compound was administered for the first time to a patient affected by rheumatoid arthritis by Philip Showalter Hench, a rheumatologist at the Mayo Clinic in Rochester, Minnesota (USA). He was investigating since 1929 the role of adrenal gland-derived substances in rheumatoid arthritis. For the discovery of cortisone and its applications in anti-rheumatic therapy, Hench, along with Edward Calvin Kendall and Tadeusz Reichstein, won the 1950 Nobel Prize for Medicine. In this review we summarize the main stages that led to the identification of the so-called compound E, which was used by Hench. We also consider the subsequent development of steroid therapy in rheumatic diseases, through the introduction of new molecules with less mineralocorticoid effects, such as prednisone, and more recently, deflazacort.

Understanding and managing periodontal diseases: a notable past, a promising future.

Throughout the 20th century, an understanding of the role of causative bacteria and the susceptible host in the initiation and progression of periodontal disease(s) has emerged from the research efforts of scientists and clinicians worldwide. Over time, specific bacterial types, such as Porphyromonas gingivalis, were discovered and shown to be important in the cause of periodontal disease. At the same time, inflammatory mediators, such as prostaglandins and interleukins, and enzymes, such as matrix metalloproteinases, were discovered and found to be important participants in the destruction of periodontal tissues. Acquired and inherited environmental risk factors began to emerge that could explain, in part, the susceptibility of individuals to periodontal disease. The discovery of antibiotics, beginning with sulfanilamide, penicillin, and streptomycin, led to additional strategies for managing periodontal disease. With the discovery of the mechanism of action of aspirin, scientists began to develop new strategies for treating diseases that focused on controlling inflammation. Thus, host-modulating therapies emerged for the management of periodontal disease through the control of inflammation. At the end of the 20th century, an old concept in medicine and dentistry reappeared: that the infection and inflammation of periodontal disease in the mouth could reach distant sites via the bloodstream. Apparently oral disease could, in fact, contribute to systemic diseases, such as atherosclerosis, diabetes, and adverse outcomes in pregnancy. This concept of the oral health-general health connection is now supported by sound and rational evidence-based observations. Clearly, the 21st century has arrived with a new understanding of the nature of periodontal diseases based on a notable era of discovery. There is a promising future for preventing and treating this common and troubling condition that affects not just the mouth but also the whole body.

Simvastatin: two decades in a circle.

Simvastatin is an agent of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor group of drugs. It is administrated orally once a day in doses of 5-80 mg. Although its main action is to reduce total and low-density lipoprotein (LDL) cholesterol, it is able to reduce triglycerides and increase high-density lipoprotein cholesterol levels, though at a lower extent. Beyond this action, studies enrolled with simvastatin have shown beneficial effect on endothelial function, smooth muscle cell function, hemostasis, vascular wall function, LDL oxidation, and inflammation. All these actions mentioned above are known as pleiotropic effects. In this review, we will present all these effects, as well as the beneficial effects on atherogenesis and the reduction in cardiovascular morbidity and mortality related to simvastatin.